FDA, Sponsors Seek to Strengthen PDUFA

The Food and Drug Administration's Prescription Drug User Fee program (PDUFA) has to be reauthorized by October 1, 2007, and all of the interested parties are fine-tuning their wish lists for "improvements." Although some consumer advocates and their Congressional allies blast user fees for extending industry control over the drug approval process, FDA officials, pharma companies, and patient disease groups applaud the program's success in ending "drug lag" and speeding new therapies to market.

Jill Wechsler

FDA held a meeting in November to open the PDUFA 4 debate. The added resources from user fees over the last decade have improved the NDA approval process, observed Steven Galson, director of the Center for Drug Evaluation and Research (CDER). Most new drug applications (NDAs) need only one review cycle to gain approval, he pointed out, and the scientific expertise of CDER's staff has improved noticeably.

FDA Acting Commissioner Andrew von Eschenbach termed PDUFA reauthorization "critical" to FDA's ability to make "biomedical innovation a reality." Deputy Commissioner Janet Woodcock described how user fees support a broad range of FDA activities from early discovery through post-market surveillance and how the program has been expanded twice since 1992 to support more interaction with sponsors and to modernize agency information systems.

Seeking flexibility

Now FDA wants more flexibility to use fee revenues to further extend drug safety oversight and to review DTC advertising before it goes public. The agency also would like to devote some of its added resources to improve the increasingly complex drug development process as part of its Critical Path Initiative. An FDA white paper lays out the agency's case for more appropriations, in addition to user fees, to support the agency's ever-growing responsibilities [available at www.fda.gov/oc/pdufa].

FDA cites an expanded workload to justify fee revisions: while NDAs and biologics license applications (BLAs) have been fairly flat, efficacy and manufacturing supplements continue to rise. A major challenge for the agency is to schedule and plan for a growing number of sponsor-requested meetings, which totaled about 2000 last year. FDA also assessed nearly 350 special research protocols, many involving innovations in clinical trial design. This surging volume of assessments and meetings are considered important for improving the drug development process, but consume considerable agency resources that FDA claims

are not included fully in PDUFA workload calculations.

No Christmas trees

Pharma companies basically want to renew PDUFA but hold the line on fee increases and the use of fee revenues for activities unrelated to drug development and market approval. Sponsors now pay a fee of almost $800,000 to file an NDA or BLA, an amount spurring proposals for more waivers and reduced fees for small companies and orphan drug developers.

The broader goal is to prevent a PDUFA reauthorization bill from becoming a "Christmas tree" loaded with legislation peripheral to the drug approval process. Measures to spur development of follow-on biologics, to establish new drug safety oversight arrangements, to mandate completion of postapproval studies, and to boost oversight of DTC advertising are just some of the popular proposals circulating on Capitol Hill.

However, industry supports efforts to link PDUFA reauthorization to legislation that renews incentives for studying drugs in pediatric populations, which also is up for reauthorization in 2007. The six-month patent extensions have been a boon for pharma companies, while also generating important pediatric labeling information. Generics makers object that the pediatric patent extensions only boost drug costs for everyone, but find themselves opposed by doctors who applaud the new pediatric formulations and useful prescribing information generated by the program.

Before talking about more fees, Abbott Senior Vice President Bruce Burlington, representing PhRMA (Pharmaceutical Research and Manufacturers of America) at the November meeting, urged further analysis of whether current user fee revenues are wisely spent. Industry expressed support for continued development of FDA computer information systems, but Alison Lawton of the Biotechnology Industry Organization (BIO) questioned whether FDA's continuous market application pilot programs have been successful and are worth continuing.

Overall, sponsors are concerned that increasing clinical development times for new drugs have offset reductions in NDA approval times under PDUFA and actually are delaying when new drugs come to market, commented Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development. Burlington and Lawton noted that an FDA study of which applications gain approval in one review cycle and which take longer may be informative.

Support for safety

Lawton of BIO also suggested that one way to improve drug safety may be to improve FDA's evaluation of trade names. This may fit FDA's desire to make more user fee revenues available to support expansion of FDA's postmarketing surveillance and risk management activities, which have been under intense scrutiny by Congress and the public for the last two years. Under PDUFA 3, FDA can allocate user fee revenues for drug safety monitoring during the first two years a new drug is on the market (three years for potentially dangerous medications). However, the agreement covers only new drugs, and not safety issues related to products approved five or ten years ago, such as most COX-2 inhibitors and antidepressants. In the last decade, FDA has experienced a big increase in the number of individual adverse event reports it receives, and Galson pointed out that CDER staff actually devotes 50% of its time to drug safety activities, a figure that includes the assessment of safety studies in NDAs.

More flexibility could provide resources for FDA to implement some of its recently proposed initiatives to increase product surveillance, improve its ability to communicate safety concerns to the public, and better organize its internal postmarketing oversight operation. However, pharma companies and health professionals have voiced reservations about some of these proposals. At a two-day meeting in December on FDA methods for communicating drug risk information, manufacturers, pharmacists, and other parties complained about the proliferation of agency "risk communication tools." Today, labeling changes may be announced through FDA press releases, talk papers, public health advisories, MedWatch safety updates, health care professional information sheets, and patient information sheets (PISs). For example, a recent notice on the risk of birth defects with Paxil (paroxetine) appeared in an FDA press release, a public health advisory, an alert for health professionals, and a PIS.

Manufacturers are particularly upset by FDA's plan to post "emerging" drug safety information on a new Drug Watch Web site. Industry representatives described the plan to make early adverse event signals publicly available as likely to confuse both consumers and physicians about whether a drug is unsafe and should no longer be prescribed. In response, agency officials plan to "go back and rethink" the proposal, according to Galson of CDER, who recently termed the Drug Watch proposal "one of the most challenging policy issues" before the agency.

Push for appropriations

One area of agreement between FDA and industry is that the agency desperately needs a significant increase in appropriated funding to prevent the whole PDUFA program from collapsing. This year, pharmaceutical and biotech companies will pay about $250 million in fees for applications, products, and facilities, exceeding by about $50 million the portion of appropriated funds devoted to drug review activities. The situation undermines the complex "trigger" arrangement established in 1992 to ensure that user fees would be additive to FDA appropriations and not merely replace public funding, an arrangement backed by all parties.

A main budget problem is that FDA appropriations seldom cover mandated cost-of-living increases, which run about 5% to 6% annually. While the number crunchers so far have provided FDA with enough appropriated funds to trigger user fee collections each year, the continued squeeze on FDA's budget challenges the program's basic principle.

Some relief could come from user fees on other regulated products. FDA has launched similar discussions involving reauthorization of user fees for medical device manufacturers, which also expire in 2007. Officials at FDA's Center for Devices and Radiological Health (CDRH) also seek to use more of the fees collected under the Medical Device User Fee and Modernization Act (MDUFMA) of 2002 for postmarket surveillance, a proposal gaining momentum following recent safety crises involving devices.

FDA also could gain more revenue from user fees on generic drugs. This long-discussed proposal resurfaced in recent months, as prospects have dimmed for budget increases earmarked for FDA's Office of Generic Drugs. Generics makers say they're willing to discuss the idea, but application fees for abbreviated NDAs are tricky due to often lengthy delays between approval and when the product comes to market. More user fees, however, are unlikely to ever provide the resources FDA needs to fulfill its mission and multiple mandates.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com